Biotechnology has revolutionized the way of life on earth. The Modern biotechnology approaches have been instrumental in developing genetically modified organisms (GMOs) that are now frequently being used in most of the major industries, particularly in food and agriculture. It is evident that these GMOs have increased the production and productivity and brought in many positive incentives in many industries. Since these genetic modifications involve the transfer of genetic material between widely unrelated organisms, despite the benefits, concerns have risen over the use of GMOs with respect to environmental safety, human and animal health, and several other social, ethical, and cultural aspects. Among which, food safety and the impact of GMOs on biodiversity are two key areas of concern. Given the concerns, ensuring the safe use of GMOs has become one of the major global discussions of the past few decades. Since its first attempt in the early 1970s, ensuring biosafety of GMOs has evolved and strengthened with the addition of numerous regulatory instruments, with the Cartagena Protocol on Biosafety acting as the main legally binding global protocol on ensuring biosafety. The national biosafety regulatory frameworks vary across countries depending on the extent of utilization of GMOs and related products and the extent of biotechnology research conducted. Developing and practicing biosafety regulations has become a timely need as it ensures the sustainable utilization of genetic resources. This chapter summarizes the current status and prospects of the national biosafety regulatory systems of the countries in the South Asian region. Furthermore, the chapter discusses the main challenges and the way forward in implementing and improving national biosafety regulatory systems.